Acute attacks of migraine are usually treated with a peripheral vasoconstrictor, such as ergotamine, which may be co-administered with caffeine, and dihydroergotamine; an antipyretic analgesic, such as acetylsalicylic acid or p-acetylaminophenol; and/or an anti-emetic such as cyclizine, metoclopramide and thiethylperazine. It has also been reported (J. B. Hughes; Med. J. Aust. 2, No. 17, 580, 1977) that immediate relief of acute migraine attack can be obtained by slow intravenous injection of metoclopramide (10 mg).
It is believed that 5-hydroxytryptamine (5-HT) is the naturally occuring substance most likely to play a role in the pathophysiology of migraine. Increased amounts of 5-HT and its metabolite 5-hydroxyindoleacetic acid are excreted in the urine during most attacks. Further, plasma and platelet 5-HT concentrations fall rapidly at the onset of an attack and remain low whilst the headache persists. Moreover, attacks of migraine have been clearly associated with periods of thrombocytopaenia in certain patients. It has been proposed that compounds which block the activity of 5-HT would be of use in the treatment of migraine (J. R. Fozard, International Headache Congress 1980) reported in Advances in Neurology, Vol 33, Raven Press, New York 1982).
The known migraine prophylactic drugs methysergide, propranolol, amitriptyline, and chlorpromazine have widely different pharmacological activities but are all 5-HT D-receptor antagonists at the doses used clinically for the treatment of migraine. Metoclopramide is a potent 5-HT M-receptor antagonist and it has been proposed (J. R. Fozard supra) that blockade of the M-receptor present on afferent sensory neurones affords symptomatic relief in an acute migraine attack.
The potency as 5-HT M-receptor antagonists of (-) cocaine and some related compounds, including pseudotropyl benzoate (i.e. benzoylpseudotropine), has been reported (J. R. Fozard et al, Eur. J. Pharmacol., 59(1979), 195-210) but, with the exceptions of nor(-)cocaine and benzoyltropine, none are as potent as metoclopramide. The pA.sub.2 values reported for pseudotropyl benzoate, nor(-)cocaine and benzoyltropine are 7.0, 7.7 and 7.2 respectively whilst the pA.sub.2 5-HT value determined for metoclopramide by the same procedure is 7.2 (J. R. Fozard et al. Eur. J. Pharmacol., 49(1978), 109-112).
It has been reported in U.S. patent application No. 386,562 filed June 9th 1982 (as yet unpublished) that substitution of tropylbenzoate (i.e. benzoyltropine) with alkyl, alkoxy or halogen in the 3, 4 and 5, or 3, 4 and 5 positions of the benzene ring surprisingly substantially enhances its potency as a 5-HT M-receptor antagonist. Tests conducted with pseudotropyl-3,5-dimethoxybenzoate (pA.sub.2 6.6) and pseudotropyl-3,4,5-trimethoxybenzoate (pA.sub.2 5.7) indicated that corresponding substitutions in the benzene ring of pseudotropyl benzoate would reduce its potency as a 5-HT M-receptor antagonist.
The present invention comprehends novel pseudotropyl benzoate derivatives having substitution by halogen in the 3, 3 and 5, or 3,4, and 5 positions of the benzene ring, which derivatives have enhanced potency as 5-HT M-receptor antagonists.